Closed loop flow control of a HPLC constant flow pump to enable low-flow operation

ABSTRACT

A method and apparatus for monitoring and controlling nano-scale flow rate of fluid in the operating flow path of a HPLC system provide fluid flow without relying on complex calibration routines to compensate for solvent composition gradients typically used in HPLC. The apparatus and method are used to correct the flow output of a typical, analytical-scale (0.1-5 mL/min) HPLC pump to enable accurate and precise flow delivery at capillary (&lt;0.1 mL/min) and nano-scale (&lt;1 μL/min) HPLC flow rates.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 11/569,301,filed on May 13, 2008, now U.S. Pat. No. 7,674,375, which is theNational Stage of International Application No. PCT/US05/17923, filedMay 20, 2005, which claims priority to and benefit of ProvisionalApplication Ser. No. 60/573,528, filed May 21, 2004. The entire contentsof these applications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a flow sensing method and apparatus andmore particularly to a flow sensing method and apparatus used to monitorand provide feedback to a closed-loop flow control of ananalytical-scale high performance liquid chromatography (HPLC) systemwhich enables the delivery of stable flow to a nano-scalechromatographic system using a micro-scale or normal scalechromatographic pump.

BACKGROUND OF THE INVENTION

The recent interest in nano-scale chromatography (<1 μL/min flow rates)has prompted HPLC instrument manufacturers to try to develop pumpscapable of delivering lower flow rates. Unfortunately, typicalanalytical-scale HPLC pump technology does not scale well to these lowflow rates as the constant-flow open-loop analytical-scale pumpstypically used for analytical-scale chromatography (0.1-5 mL/min) aregood flow sources above ˜0.1 μL/min, but below these flow rates,inaccuracies due to solvent compression and seal, fitting or check-valveleakage compromise their flow accuracy.

Traditional plunger displacement pumping systems have been successful indelivering stable, accurate flows in the normal-scale and micro-scalehigh performance liquid chromatography regimes. While normal-scale HPLCis performed with mobile phase flow rates of about 0.1-5.0 mL/min andmicro-scale HPLC is performed with mobile phase flow rates of about1-100 μL/min, nano-scale HPLC requires mobile phase flow rates in the50-1000 nL/min range. Current plunger displacement pumping systemstypically cannot deliver nano-scale HPLC flow rates with reliability andaccuracy.

One method for providing nano-scale flow rates in an HPLC system is touse a flow-divider which directs a majority of flow from the pump to awaste stream and a small portion of the pump output to the HPLC workingstream (i.e., to the liquid chromatography column). A split restrictorin the waste stream and/or the working stream controls the split ratioof the system. Normal-scale or micro-scale HPLC pumps can be used insplit flow mode to produce nano-scale HPLC flow rates in the workingstream.

Unfortunately, in order to operate a HPLC system in split-flow mode theuser must calculate the split ratio of the system. To calculate thesplit ratio, the user must know the permeabilities of both the splitrestrictor and the chromatographic system (i.e. the packed column).These permeabilities are used to calculate the flow rate that must besupplied by the normal-scale or micro-scale HPLC pump to produce thedesired flow through the chromatographic system. Although it is possibleto calculate split restrictor dimensions that should provide a desiredsplit ratio, changes in permeability of either the split restrictor orchromatographic column over time cause unpredictable split ratiovariations. Such variations result in unacceptable flow variationsthrough the chromatographic column.

One possible solution to the problem of changing split ratios is tomonitor the flow to the chromatographic column with an appropriate flowsensor. Fluid flow rates can be determined by measuring the pressure ofa liquid flowing through a restrictor. Assuming a constant viscosity,the back pressure of liquid flowing through a restrictor will scalelinearly with the flow rate of the liquid. The flow rate is measured byplacing a pressure transducer before and after a restrictor inline withthe flow. Signals from the pressure transducers are electronicallysubtracted and amplified to achieve a high degree of common-mode noiserejection.

The permeability of the restrictor is chosen so that it providessufficient back pressure to produce a measurable pressure differencesignal (ΔP) in the flow ranges of interest but does not produce asignificant back pressure for the pump. For example, a 10 cm long, 25 μminside diameter capillary will provide a back pressure of approximately100 pounds per square inch (psi) for water flowing at 5 μL/min. Thispermeability is sufficient for providing a flow measurement while notinducing much fluidic load on the pump.

However, pressure measuring flow sensors must be calibrated tocompensate for the different viscosity of each fluid being measured.This creates a great disadvantage in liquid chromatography applicationswherein fluid composition varies dramatically over the course of achromatography run.

Another method that can be used to sense fluid flow is thermal flowsensing. Several companies including Sensirion AG, of Zurich,Switzerland, and Bronkhorst Nijverheidsstraat of Ruurlo, TheNetherlands, have been developing thermal flow sensors capable ofmonitoring flows in nL/min ranges.

In the operation of these thermal flow sensors, heat introduced into aliquid filled tube/channel will disperse in both the upstream anddownstream directions (i.e. due to thermal conduction or diffusionrespectively). The tube of the flow sensing device is made frommaterials of low thermal conductivity (i.e. glass, plastic). Atemperature profile will develop when a discrete section of the fluid inthe tube is continuously heated, under a zero flow condition. The shapeof this temperature profile will depend upon the amount of heat added tothe fluid and the upstream and downstream temperatures of the liquid.Assuming identical upstream and downstream fluid temperatures, under azero-flow condition, liquid temperatures measured at first and secondsensor will be equal as thermal diffusion will be equal in bothdirections.

If the liquid in the tube is permitted to flow, the fluid temperaturesat the first and second sensor will depend upon the rate of liquid fluxand the resulting heat convection. As liquid begins to flow past theheated zone, a temperature profile develops. In addition to thesymmetric diffusion of the heat, asymmetric convection of the heatedfluid will occur in the direction of the fluid flow. Therefore, underflowing conditions, fluid temperatures measured at the first and secondsensor will be different.

Temperature measurements made at the first and second sensor aresampled, subtracted and amplified electronically in situ to provide ahigh degree of common-mode noise rejection. This allows discriminationof extremely small upstream and downstream temperature differences. Byappropriate placement of temperature measurement probes (i.e., first andsecond sensor) and/or by changing the amount of heat added to theflowing liquid, temperature measurement can be made at inflection pointsalong the temperature profile. Measurement at the inflection pointsmaximizes the upstream/downstream ΔT response to flow rate change.

However, like pressure measuring flow sensors which must be calibratedto compensate for the different viscosity of each fluid being measured.Thermal based flow sensors also need such calibration. This at timescreates a disadvantage in liquid chromatography applications whereinfluid composition varies dramatically over the course of achromatography run.

Other pump solutions for creating the low flow rates required bynano-scale LC involve single-stroke syringe pumps. These pumps have afixed delivery volume. As a result run times may be limited by thelength of the pump stroke. Time is required between each run to refillthe pump. During this refill cycle, the chromatographic system mustdepressurize, then re-pressurize to start the next run. Repeateddepressurization/re-pressurization cycles unfortunately have adeleterious effect on the chromatographic column.

Additionally, Nano-scale LC systems are often coupled to massspectrometers. Electro-spray interfaces typically used in LC-coupledmass spectrometers are most stable when constantly flowing. Thestop-flow conditions existing during refill cycles of syringe-type pumpsas noted above may destabilize the electro-spray mass spectrometryinterface.

SUMMARY OF THE INVENTION

Some embodiments of the present invention involve a method and apparatusfor monitoring and controlling the nano-scale flow rate of fluid in anoperating flow path of a HPLC system without relying on complexcalibration routines to compensate for solvent composition gradientstypically used in HPLC. According to some of these embodiments of theinvention, an apparatus and method is used to correct the flow output ofa typical, analytical-scale (0.1-5 mL/min) HPLC pump to enable accurateand precise flow delivery at capillary (<0.1 mL/min) and nano-scale (<1μL/min) HPLC flow rates.

According to one embodiment of the invention, the analytical-scaleconstant flow-source HPLC pumps used are modified commercially availablepumps. These commercially available pumps are retro-fitted with minorhardware and/or firmware changes to enable low-flow delivery. Typically,analytical-scale HPLC pumps use stepper-motor driven linear actuators.Depending on the pump architecture, the change required to enablelow-flow delivery involves modifying the gearing of the pump drivemechanism offering a higher incremental drive resolution. According toone embodiment of the invention, changes to the firmware/stepper motordrive electronics increasing the micro-stepping resolution of thestepper motor drive is contemplated. It is envisioned, for example, thatminor modifications to the pumps firmware by increasing themicro-stepping resolution from 10 μSteps to 100 μSteps enables low-flowoperation.

In a first illustrative embodiment, delta-P type flow meters, as in-linesensors, are used within the inventive apparatus. Fluid flow from afirst pump in an operating path flows through an initial in-linepressure transducer and through a restriction element and is mixed withfluid flow from a second pump within a second operating path having asecond in-line sensor and restriction element at a fluidic cross.Pressure at this fluidic cross is measured by a fluidic cross pressuretransducer. According to the invention, a pressure drop measured betweenthe first and second inline flow sensors and the pressure at the fluidiccross will be proportional to the flow delivered by the first and secondpumps respectively. While delta-P flow sensors typically require twopressure transducers for each flow line, the inventive fluidic crosspressure transducer arrangement allows the fluidic cross transducer tobe used by each respective flow line. The use of a common fluidic crosstransducer at the fluidic cross eliminates the need for four pressuretransducers.

In another illustrative embodiment of the invention, an apparatus fordelivering a liquid in a capillary system includes two flow-source pumpsand two associated thermal sensors. Advantages of the invention includecorrection of the flow output of a typical, analytical-scale (0.1-5mL/min) HPLC pump enabling accurate and precise flow delivery atcapillary (<0.1 mL/min) and nano-scale (<1 μL/min) HPLC flow rates. Thepresent invention permits retrofitting and reuse of existing pumptechnology providing cost and supply advantages.

A further advantage of the inventive apparatus and method is there aresignificant advantages to reusing existing pump technology with the flowcorrecting apparatus according to the invention. These advantagesinclude cost savings associated with development, sales and servicetraining and inventory management. Furthermore, traditionalconstant-flow HPLC pumps are ideally suited for use according to theinvention.

Another further advantage of the inventive apparatus and method isbecause constant flow pumps are used, calibration of the flow sensorscan be accomplished easily by flowing know flow rates through thesensors to determine their response. This calibration routine accordingto the invention can be done at relatively low pressures where pumpleakage and solvent compressibility is not an issue, and steadyopen-loop flow delivery can be expected. Because a known flow rate isbeing delivered by the constant-flow pumps, the error between thisdelivered flow and the flow measured by the flow sensors can be used todiagnose pump leakages. Intelligence can be implemented according to theinvention to correlate flow error with the pump cycle to identify whereleakages were occurring. Advantageously, this level of diagnostics isextremely useful not only for troubleshooting pump failure, but earlydiagnosis and suggested corrective action to prevent pump failure.

A further advantage of the inventive method and apparatus is continuousflow operation is possible using typical constant-flow HPLC flowsources. Advantageously, all limitations resulting from stop-flowconditions can be avoided.

BRIEF DESCRIPTION OF THE DRAWING

The foregoing and other features and advantages of the present inventionwill be more fully understood from the following detailed description ofillustrative embodiments, taken in conjunction with the accompanyingdrawing in which:

FIG. 1 is a schematic representation of a closed-loop flow controlbinary solvent delivery system using temperature stabilized delta-P flowsensors, according to the invention.

DETAILED DESCRIPTION

Detailed embodiments of the present invention are disclosed herein,however, it is to be understood that the disclosed embodiments aremerely exemplary of the invention, which may be embodied in variousforms. Therefore, specific functional details disclosed herein are notto be interpreted as limiting, but merely as a basis for the claims andas a representative basis for teaching one skilled in the art tovariously employ the present invention in virtually any appropriatelydetailed embodiment.

Some embodiments of the invention involve one or more flow sources. A“flow source” is herein understood to be a source that provides a fluidhaving a flow rate associated with a volume per unit of time. Forexample, one type of flow source includes a piston that displaces avolume of fluid per unit of time. A particular value of volume per unitof time is determined, for example, by controlling the linear velocityof the piston, and by selecting a piston diameter, in the case of apiston having a circular cross-section. Thus, for example, the velocityof the piston multiplied by the area defines a volumetric flow rate.This flow rate is analogous to, for example, a current source in anelectrical circuit, which provides an amount of charge per unit of time.

A flow source is distinct from a pressure source, such as a pneumaticair supply with a regulator. A pressure source is analogous to, forexample, a voltage in an electrical circuit. Pressure (voltage, in theanalogy) induces a particular flow rate (a current in the analogy) ifimpressed upon a fluid restriction (a resistor, in the analogy). Thus,while a flow source has the ability to independently determine a flowrate, a pressure source typically does not independently determine aflow rate. Rather, a pressure source works in cooperation with othercomponent(s) of a flow path, such as a flow-restrictor component, todetermine a flow rate through the flow path.

Turning to FIG. 1, a schematic of a closed loop system 100 according tothe invention is shown. A first pump 102 and a second pump 104, whichare flow-source pumps such as, for example, analytical-scale constantflow-source HPLC pumps. These analytical-scale constant flow-sourcepumps are any suitable pumps such as commercially available pumps (forexample, the WATERS® 515, 1525u, and Acquity pumps, available fromWaters Corporation, Milford, Mass., USA, or the like.) The first pump102 and second pump 104 are fitted with minor hardware and/or firmwarechanges to enable low-flow delivery. Typically, analytical-scale HPLCpumps use stepper-motor driven linear actuators. Depending on the pumparchitecture, change required to enable low-flow delivery involvesmodifying the gearing of the pump drive mechanism. These modificationsto the gearing of the pump drive mechanism offer a higher incrementaldrive resolution. It is contemplated within the scope of the inventionthat changes to the firmware/stepper motor drive electronics to increasethe micro-stepping resolution of the stepper motor drive may be used toenable low-flow delivery. In a first illustrative embodiment, minormodifications to the pumps' firmware are made by increasing themicro-stepping resolution from about 10 μSteps to about 100 μSteps. Thisincreased resolution allows low-flow operation.

While it may be possible to develop a pump specifically designed todeliver flow compatible with nano-scale LC, there are significant costand supply advantages to reusing existing pump technology with the flowcorrecting apparatus described above. Advantageously, traditionalconstant-flow HPLC pumps are ideally suited for this application.

With further reference to FIG. 1, the first pump 102 is in fluidcommunication to a first inline sensor 106. The first inline sensor 106in a first illustrative embodiment is a delta-P type pressuretransducer. In this first illustrative embodiment the pressuretransducer used is a DJ model DF Thruflow pressure transducer, DJInstruments, Billerica, Mass. It is contemplated within the scope of theinvention that any flow sensors capable of providing precise andaccurate output signals in the micro-scale flow range can be used toimplement the flow sensing according to the illustrative embodiment ofthe invention. In particular, it is contemplated within the scope of theinvention that other types of flow sensors may be used including but notlimited to thermal-based flow sensors, available from, for example,Bronkhorst High-Tech B.V., Ruurlo, The Netherlands, and Sensirion AG,Zurich, Switzerland.

As shown in FIG. 1, in a first operating path 101 flow from the firstpump 102 is in fluid communication with the first inline sensor 106. Thefirst inline sensor 106 is in fluid communication with a firstrestriction element 108. The first restriction element 108 is in fluidcommunication with a fluidic cross 110. In a second operating path 103,the second pump 104 is in fluid communication with a second inlinesensor 112. The second inline sensor 112 in the first illustrativeembodiment is a pressure transducer. The second inline sensor 112 is influid communication with a second restriction element 114. The secondrestriction element 114 is in fluid communication with the fluidic cross110. Pressure at the fluidic cross 110 is measured by a fluidic crosssensor 116. The fluidic cross sensor 116 in a first illustrativeembodiment is a pressure transducer.

In operation, a pressure drop measurement between the first inlinesensor 106 and the fluidic cross sensor 116 and the second inline sensor112 and the fluidic cross sensor 116 will be proportional to the flowdelivered by the first pump 102 and the second pump 104 respectively.

While delta-P flow sensors typically require two pressure transducersfor each flow line, the inventive configuration having three sensors106, 112, 116, which in a first illustrative embodiment are pressuretransducers, allows the fluidic cross sensor 116 to be used by bothoperating paths 101, 103. This configuration according to the inventioneliminates the need for four pressure transducers. It is contemplatedwithin the scope of the invention, however, that each operating path101, 103 could have two sensor that are pressure transducers. It isfurther contemplated within the scope of the invention that eachoperating path 101, 103 can have only one flow sensor producing a firstand second flow signal.

In operation, a system controller 120 will interpret pressures measuredby the sensors 106, 112 and 116 using previously obtained calibrationconstants and calculate flow rates being delivered by the first pump 102and second pump 104. The system controller 120 will modify flow ratesdelivered by the pumps 102, 104 to adjust for any error between measuredflow rates and set point flow rates. Using the inventive method, flowinaccuracies resulting from solvent compressibility, pump or systemleakage are corrected.

In the first illustrative embodiment of the invention, output from thesensors 106, 112, 116 are used to control the flow rate in therespective operating paths 101, 103. FIG. 1 illustrates the firstembodiment of the invention where the flow rate in the operating paths101, 103 is controlled by calculating the pressure drop differencebetween inline sensors 106, 112 with that of the fluidic cross sensor116 and adjusting flow rate of the first pump 102 and second pump 104proportionately. Persons having ordinary skill in the art shouldappreciate that additional control circuitry (not shown) may be requiredbetween the output of the sensors 106, 112, 116 and the input of thepumps 102, 104. For example, additional control circuitry may beimplemented to condition the output signal for use as an appropriatecontrol input to the particular pump being used. Circuit components suchas buffers, inverters, amplifiers and/or microcontrollers, for example,can be used to implement the control circuitry according to a number ofmethods that are well known to those skilled in the art.

In the first illustrative embodiment of the invention the controller120, a microcontroller or microprocessor, is implemented between thepressure transducer output and the control input of the respective pumps102, 104. The controller 120 can be programmed and configured, forexample, to adjust the flow rate of the pumps 102, 104 to a settingappropriate for maintaining a respective flow rate producing a selectedgradient composition.

When using delta-P type pressure transducers as flow sensors, in orderto obtain accurate flow measurements using differences in the threesensors 106, 112, 116, it is desirable that the zero point of eachsensor 106, 112, 116 be maintained at a constant. A common source ofzero point drift in strain-gage pressure transducers is transducertemperature fluctuations. Strain-gage pressure transducers measurechanges in the resistance of strain elements to determine pressure. Thestrain element's resistance will also change with temperature. If one ormore of the three pressure transducer's, used as sensors 106, 112, 116,zero point changes due to temperature fluctuations, differencecalculations used to measure flow rate will be inaccurate. Forconsistent and reproducible results the three pressure transducers usedas sensors 106, 112, 116, in a first illustrative embodiment, may becontained in a first isothermal block 122. In addition, the restrictionelements 108, 114 used in conjunction with the sensors 106, 112, 116 mayalso be maintained in a second isothermal block 124. The temperature ofthe restriction elements 108, 114 must be maintained at approximatelythe temperature they were calibrated. Changes in the temperature of therestriction elements 108, 114 will result in erroneous flow measurementsas temperature-induced viscosity changes of the fluid inside therestriction elements 108, 114 change the pressure difference across theflow restriction element 108, 114. While the sensors 106, 112, 116 andthe flow restriction elements 108, 114 can be maintained at isothermaltemperature, it is not necessary that they are maintained at the sametemperature.

Flow sensors used in the inventive flow-correcting apparatus will needto be calibrated for the each solvent used in the system.Commercially-based thermal flow sensors have different responsesdepending on the thermal capacity of the measured fluid. Delta-P typeflow sensors are sensitive to solvent viscosity. Because constant flowpumps are used in this system, calibration of these flow sensors can beaccomplished easily by flowing known flow rates through the sensors todetermine their response. This calibration routine can be done atrelatively low pressures where pump leakage and solvent compressibilityis not an issue, and steady open-loop flow delivery can be expected.

Because a known flow rate is being delivered by constant-flow pumps, theerror between the delivered flow and the flow measured by the flowsensors can be used to diagnose pump leakages. It is contemplated withinthe scope of the invention that system intelligence can be implementedin the flow controller 120 to correlate flow error within the pump cycleidentifying where leakages are occurring. In typical two-plungerreciprocating or serial flow delivery pumps, flow errors can becorrelated to the seal or check valve responsible for the leakage. Thislevel of diagnostics allowed by such system intelligence according tothe invention is useful for troubleshooting pump failure allowing forearly diagnosis and suggested corrective action preventing costly pumpfailure.

Other pump solutions for creating the low flow rates required bynano-scale HPLC involve single-stroke syringe pumps. These pumps have afixed delivery volume. As a result run times may be limited by thelength of the pump stroke. Time is required between each run to refillthe pump. During this refill cycle, the chromatographic system mustdepressurize, then re-pressurize to start the next run. Repeateddepressurization/re-pressurization cycles may have a deleterious effecton the chromatographic column. Nano-scale LC systems are often coupledto mass spectrometers. Electro-spray interfaces, used in LC-coupled massspectrometers, are most stable when constantly flowing. The stop-flowconditions existing during refill cycles of syringe-type pumps maydestabilize the electro-spray mass spectrometry interface. When usingthe inventive apparatus and method described herein, continuous flowoperation is possible using constant-flow HPLC flow sources. Thus alllimitations resulting from stop-flow conditions can be avoided.

By using analytical-scale continuous flow HPLC pumps, high flow ratescan be used to prime the system when solvent change over is necessary.For nano-flow systems that employ low-flow only pumps, this primingoperation may take a significant amount of time.

Although sensors are described herein in terms of specificpressure-type, delta-P, flow sensors or thermal base flow sensors,persons skilled in the art should appreciate that any number of variousflow sensor types may be substituted therefor without departing from thespirit and scope of the present invention. For example several types ofcommercially available sensors or the like can be used as in-line flowsensors according to the present invention. Likewise in embodimentsusing sensors other than pressure-type sensors, each flow path maycontain a singular flow sensor controlling the output of its respectivepump or pressure source.

Although flow sensors are described herein in terms of being in fluidcommunication with a flow sense restrictor, persons skilled in the artshould appreciate that the sensors described herein may be used withoutflow sense restrictors without departing from the spirit and scope ofthe present invention.

In another illustrative embodiment of the invention, a system optionallyincludes fewer components than the embodiment described above withreference to FIG. 1. This alternative system includes two flow-sourcepumps and two associated thermal sensors. Flow restrictors and a crosssensor are not, however, included in this alternative embodiment.

This alternative embodiments has several potential advantages. Forexample, parasitic losses that at times arise due to pressure-typesensors are avoided.

Although various embodiments of the present invention are describedherein in terms of separate circuit components for comparing pressurefrom various sensor components, persons skilled in the art shouldappreciate that a single circuit component can be implemented to servemultiple comparison functions according to the present invention. Forexample, a single microcontroller having multiple measurement inputports and control output ports can be used to receive and process firstpressure drop and second pressure drop signals to compute desired pathflow rates and generate output signals for communicating to the firstand second pumps. An application specific integrated circuit (ASIC)could also be designed, for example, to perform these functions as wellas incorporating the functions of the pumps, either by digital or analogoperation, without departing from the spirit and scope of the presentinvention.

Although embodiments of the present invention are described herein whichcontrol flow rates in the respective operating paths by controlling thepump, persons skilled in the art should appreciate that these variouscontrol elements could be also implemented in various combinationsaccording to the present invention.

Although the various embodiments of the present invention are describedfor use in measuring nano-scale flow rates in an HPLC system, personsskilled in the art should appreciate that the present invention can beused to measure and control a variety of different capillary systems, orfluid control and analysis systems without departing from the spirit andscope of the invention.

Although the invention is described hereinbefore with respect toillustrative embodiments thereof, persons having ordinary skill in theart should appreciate that the foregoing and various other changes,omissions and additions in the form and detail thereof may be madewithout departing from the spirit and scope of the invention.

What is claimed is:
 1. An apparatus for delivering a liquid in achromatography capillary system comprising: a first pump in fluidcommunication to a first flow path carrying a first portion of a liquidfrom said first pump to a first thermal-based flow sensor containedwithin an isothermal block, said first thermal-based flow sensor beingoperatively disposed in said first flow path and configured to produce afirst signal corresponding to a flow rate of said first pump; a secondpump in fluid communication to a second flow path carrying a secondportion of a liquid from said second pump to a second thermal-based flowsensor contained within said isothermal block, said second thermal-basedflow sensor being operatively disposed in said second flow path andconfigured to produce a second signal corresponding to a flow rate ofsaid second pump; and means for controlling flow rates within each flowpath in response to said first and second flow-rate signals, the meansfor adjusting comprising a system controller configured to adjust theflow rates of said first and second pumps proportionately.
 2. Theapparatus according to claim 1 wherein the first pump comprises a afirst flow source, and the second pump comprises a second flow source.3. The apparatus of claim 2 wherein the first flow source comprises apiston.
 4. The apparatus of claim 3 wherein the first flow source isconfigured to provide a particular flow rate in response to a velocityof the piston and a surface area of the piston.